Nefarious neutrophil cytoplasts

In addition to DNA release, neutrophil extracellular trap (NET) formation can result in enucleated cells called cytoplasts. Krishnamoorthy et al. examined how neutrophil cytoplasts contribute to asthmatic inflammation in mouse models of allergic lung inflammation and in asthmatic patients. Airway exposure of mice to LPS with house dust mite allergen induced NET formation in the lung that was associated with IL-17 production upon subsequent exposure to allergen. Cytoplasts and not neutrophil DNA released in NETosis triggered neutrophilia upon allergen exposure, and cytoplasts alone were sufficient to induce IL-17 production by antigen-specific T cells. Cytoplasts also correlated with IL-17 levels in bronchoalveolar lavage fluid from severe asthmatics. These findings provide insight into how neutrophil cytoplasts can contribute to asthma severity.

Abstract

Severe asthma is a debilitating and treatment refractory disease. As many as half of these patients have complex neutrophil-predominant lung inflammation that is distinct from milder asthma with type 2 eosinophilic inflammation. New insights into severe asthma pathogenesis are needed. Concomitant exposure of mice to an aeroallergen and endotoxin during sensitization resulted in complex neutrophilic immune responses to allergen alone during later airway challenge. Unlike allergen alone, sensitization with allergen and endotoxin led to NETosis. In addition to neutrophil extracellular traps (NETs), enucleated neutrophil cytoplasts were evident in the lungs. Surprisingly, allergen-driven airway neutrophilia was decreased in peptidyl arginine deiminase 4–deficient mice with defective NETosis but not by deoxyribonuclease treatment, implicating the cytoplasts for the non–type 2 immune responses to allergen. Neutrophil cytoplasts were also present in mediastinal lymph nodes, and the cytoplasts activated lung dendritic cells in vitro to trigger antigen-specific interleukin-17 (IL-17) production from naïve CD4+ T cells. Bronchoalveolar lavage fluid from patients with severe asthma and high neutrophil counts had detectable NETs and cytoplasts that were positively correlated with IL-17 levels. Together, these translational findings have identified neutrophil cytoplast formation in asthmatic lung inflammation and linked the cytoplasts to T helper 17–mediated neutrophilic inflammation in severe asthma.